There are compelling theoretical reasons for early therapeutic intervention in HIV-1 infection, for this might either eliminate HIV-1 from the body completely, or lower the virological setpoint with subsequentl clinical benefit. Encouraging results from combination treatment of chronically infected patients provide a therapeutic rationale for intervention in acute and early HIV-1 infection. We plan to test combination therapy, as part of the Acute Infection and Early Disease Research Network. We propose to continue two current triple-drug trials (AZT/3TC/ritonavir/saquinavir and AZT/3TC/indinavir), and to commence at least two new trials involving four drugs (AZT/3TC/ritonavir/saquinavir and AZT/3TC/GW141/GW1592). Already, we have achieved consistent, sustained reductions in plasma viremia to <500 HIV-1 RNA copies/ml, and we will use improved assays sensitive down to 25 copies/ml to estimate the extent of viremia reduction more precisely. Some patients with persistently undetectable viremia will be offered lymphatic tissue and rectal biopsies, and genital fluid analysis, for examination on ongoing viral relication. The option to discontinue therapy will be offered based on virologic results. If virus re-emerges after cessation of treatment, or during therapy, breakthorugh virus will be characterized genotypically and phenotypically. We will also monitor cellular and humoral immune responses, to assess how reductions in viral antigen load influence the development and maintenance of effector and memory T-cell and B-cell responses. We have detected signs of antibod seroreversion, but some CTL responses persist. I may be important for treated patients to develop HIV-1 memory responses, to enable them to suppress residual virus replication permanently. To assess when immune memory develops, we will use precusor frequency assays in vitro, and determine whether anamnestic responses to HIV-1 antigens can be stimulated in vivo. We will expand our existing facilities for banking and storage of speciments, and continue to support novel therapeutic interventions in acute and/or early HIV-1 infection within the framework of the established network.